PROJECT SUMMARY/ABSTRACT The goal of this proposal is to define the signature phenotypic profiles of the two most common genetically defined forms of early onset Parkinson[unreadable]s Disease (PD), parkin (Park2) and glucocerebrosidase (GBA), cross-sectionally (Aim 1), longitudinally (Aim 2), and before motor manifestations that define PD occur (Aim 3). We will recruit 75 PD probands who carry parkin mutations, 100 PD probands who carry GBA mutations, and 100 noncarrier (idiopathic PD) probands and their first-degree relatives (3 per family). The majority of these families have participated in the Consortium on Risk for Early Onset PD (CORE PD) study, which has enrolled 1062 PD probands with age at onset (AAO) <50. In Aim 1, we will compare the range of cognitive psychiatric and motor manifestations among the three groups using the CORE PD battery. To enhance detection of cognitive and psychiatric impairment, we will use state-of-the-art computerized assessments of cognition, including interval timing, and lifetime psychopathology. In Aim 2, to refine our understanding of the prognosis for carriers of parkin and GBA, we will compare the range of cognitive, psychiatric and motor manifestations at baseline, 1.5 years and 3 years. We hypothesize that GBA PD and Parkin PD define extremes of disease progression and that GBA PD will manifest more cognitive and psychiatric impairment at baseline (Aim1) and will decline more rapidly and develop the cognitive and psychiatric features that may lead to Parkinson[unreadable]s disease dementia (PDD) significantly more frequently than parkin PD and IPD (Aim 2). In Aim 3, we will use our family history interview, video, and new web-based cognitive assessments to describe the development of motor and non-motor manifestations in first-degree relatives. We will determine the age dependent risk of developing PD (penetrance) in asymptomatic relatives who carry GBA mutations and will refine our penetrance estimates in parkin carrier relatives, particularly among Caribbean Hispanics who may have increased penetrance compared to non-Hispanic Whites. This proposal will provide medical professionals and families vital information on progression that is essential for individual treatment decisions. The penetrance estimates will help individuals decide whether to pursue genetic testing and will provide more accurate interpretation of results. Lastly, longitudinal examination of these genetic forms of PD will reduce the marked reported heterogeneity of disease progression. This will lead to improved design of clinical trials that target parkin and GBA carriers for mechanistically-driven treatments.